Antiepileptic Drugs

General Comments
Mechanisms of Action of Antiepileptic Drugs
Treating Epilepsy
Side Effects
Antiepileptic Drug Discontinuation
Drug-sparing Therapies

General Comments
This page provides a general information about the drug treatment of epilepsy in children.
Antiepileptic drugs (AEDs) are usually prescribed after a specific epilepsy syndrome diagnosis is made and the risk of subsequent seizures is known. AEDs are prescribed with the precise aim of decreasing the number, severity, and/or duration of seizures. In fact, AEDs do not cure the underlying problem predisposing to seizures, but rather attempt to prevent seizures. Factors taken into consideration when starting AEDs include the child's age, EEG findings, other medical conditions and medications the child is taking, and the potential for side effects.
Mechanisms of Action of Antiepileptic Drugs
Seizures arise from an imbalance between excitatory and inhibitory neuronal circuits in the brain, either throughout the brain (generalised or multifocal epilepsies) or in a localised part of the brain (focal epilepsy), such that neurons "fire off" in an abnormal fashion.
Seizures may be prevented by AEDs in different ways, either by decreasing excitation or enhancing inhibition. In particular, AEDs may alter both electrical activity in neurons by affecting ion (Na+, K+, Ca2+, Cl-) channels in the cell membrane and chemical transmission between neurons by affecting neurotransmitters (GABA, glutamate) in the synapses. For some drugs the mechanism of action is unknown.
How the body absorbs and removes medication is determined by the child's age and weight. Young children and adolescents have greater rates of drug clearance and are often prescribed doses per kilogram of body weight greater than an adult would receive (see Table 1).
An AED is swallowed by mouth and passes directly to the stomach. Once in the stomach the medication is absorbed into the blood stream where it is then circulated to the brain. As the drug is circulating in the blood, it is gradually removed by either the liver breaking it down (metabolism) or the kidneys filtering it out (excretion). Some drug metabolites are active and produce either beneficial antiepileptic effects or adverse side effects. Most commonly prescribed AEDs are removed from the blood at a rate that allows twice daily dosing to maintain adequate blood levels. In an emergency situation, such as status epilepticus, some AEDs can be given directly into the blood stream, into the rectum, nose or the buccal mucosa to act very quickly to control seizures.
Taking AEDs either just before or just after a meal can be a useful routine to remember to take them, and also helps the drug to be absorbed into the body.
Vomiting and diarrhoea can affect the amount of drug that is absorbed from the gut into the blood stream. This can result in low circulating levels of the drug. If vomiting occurs within minutes of taking the drug, another dose should be administered.
Some AEDs affect how other medications work and some other medications can affect how AEDs work. Hence, it is often a good idea to consult the paediatrician or pharmacist before taking any drugs.
Monitoring effectiveness
Some AEDs require regular blood level monitoring by a simple blood test. These drugs include phenytoin, phenobarbitone and carbamazepine. These blood levels are generally measured before a dose is due. Not all AEDs need to be monitored with blood levels, as there might be no good correlation between drug level and effect.
Treating Epilepsy
The aim in treating epilepsy in children is to minimize or control seizures with full respect of quality- of-life issues, especially of cognitive functions. Hence, the decision to start treating a child with epilepsy should not be rigidly made but ideally tailored to the individual patient. Around 66% (66 in 100) children will get seizure control (stop having seizures) once the best medication is found for them. This depends on the type of epilepsy they have and the appropriateness of the chosen drug.
Optimal treatment first demands correct recognition of the major type of seizures, followed by a diagnosis of the type of epilepsy or of the specific syndrome and etiology (see Table 2). In fact, AEDs can sometimes worsen seizures and this should be taken into account in choosing treatment and evaluating the ensuing clinical response (see Table 3). Seizure worsening includes aggravation of previously known seizure types, appearance of new seizure types, or precipitation of convulsive or non-convulsive status epilepticus. Knowledge of the main mechanisms of action, spectrum of efficacy, adverse effects and safety profile of AEDs is a key factor for a rational choice.
The following general principles are recommended when prescribing AEDs in children:
1) starting with a low dose and slowly increasing until seizures are controlled or the child develops toxicity
2) spacing medication doses appropriately to maintain stable blood levels
3) aiming for control of seizures with monotherapy where possible
4) giving a medication a good trial period to work before changing
5) if the drug does not control seizures, discontinuing it gradually, while a second drug is instituted and its dosage is increased
6) avoiding combinations of antiepileptic medications that are known to not interact well
To provide the best care, the physician must be familiar not only with therapeutic indications but also with tolerability and safety data.
Side Effects
All AEDs have potential side effects, so the indications for their use should be carefully weighed as one of the main objectives is controlling seizures without producing drug-related undesirable effects. Side effects can be difficult to recognise in babies and young children as they can not report exactly how they are feeling.
Monotherapy should be preferred as the interactions between AEDs are complex and variable, leading at times to unpredictable effects. Although newer AEDs do not demonstrate a superior efficacy compared to older molecules, most of them do offer some advantages in terms of tolerability, fewer interactions and simpler pharmacokinetics. However, our knowledge concerning their safety profiles can not yet be considered as adequate, due to the limited number of patients exposed to them. Particularly in children, information on AED safety is generally poor and is only acquired late, since approval for paediatric use is only granted with considerable delay, after promising results have been obtained in adults. Identifying AEDs toxicity may be particularly problematic in children with neurological co-morbidities and psychiatric and behavioural problems.
Drug-induced adverse effects (AEs) may be divided into two classes: “dose-related” or “pharmacology-related” (Type A), and “idiosyncratic” (Type B), although, at times, they do not necessarily fit either category. Most AEs of AEDs belong to the Type A category (i.e., drowsiness, fatigue, dizziness, blurry vision, and incoordination), in that they are predictable, dose-dependent, explained by the known pharmacological properties of the individual agent and usually observed at the beginning of treatment or after dose increase. They are usually reversible upon dosage adjustment and rarely require discontinuation of therapy. Type B adverse effects occur sporadically and unpredictably in susceptible individuals only, and irrespective of dosage. They include serious dermatologic, hematologic and hepatic events, which usually require withdrawal in an affected patient. Their pathogenesis is apparently unrelated to the known mechanisms of action of the offending drug, but rather represents the consequence of an abnormal, often immunological, reaction.
All medications have the possibility of causing side effects. As numerous side effects are listed against all AEDs, the neurologist and paediatrician should help you understand which are the more common or potentially serious side effects to look out for. Please refer to the specific drug information provided with your medication for a more detailed list of side effects.
Antiepileptic Drug Discontinuation
This depends on the child and the type of epilepsy or syndrome he/she has. In some syndromes seizures are known to stop around a certain age. With others, the seizures are likely to start again if medication is stopped.
Withdrawing from AEDs is best done with advice from the epileptologist as it needs to be done very slowly, often over several months. When thinking about coming off AEDs, it is important to consider the impact on your child's life if his/her seizures start again. For most children, if seizures start again, taking the same AED straight away usually gives the same seizure control as before. But sometimes the AED might not work as well as it did before.
Drug-sparing Therapies
If a child does not respond to AEDs, other treatments may be available, including ketogenic diet, epilepsy surgery and the vagus nerve stimulator.
Drug labelling frequently includes disclaimers that safety and efficacy have not been
established in neonates (birth to 28 days) and infants (29 days to 2 years). As a consequence, paediatric practice involves the use of “unlicensed” or “off-label” medicines from adults or older children. Developing drugs specifically for children is particularly important because paediatric diseases are different from those of adults in terms of aetiology, mechanisms, clinical or biological features, and course.
There is a tremendous need for trials in children with epilepsy. Both pharmacokinetic and safety data are required at any paediatric age.
Pharmacoresistant epilepsies, which occur at any age in the paediatric population, have no equivalent in adulthood. Therefore, no extrapolation from data collected in adults is possible, particularly for infantile epilepsies, that remain “therapeutic orphans” despite the fact that they represent the most deleterious conditions in the area of epilepsy.
Epileptic encephalopathies represent about one-half of the pharmacoresistant epilepsies in the paediatric age range, the other half being focal epilepsy. Epileptic encephalopathies are age-related, the best identified syndromes are West syndrome (infantile spasms), Dravet syndrome, Lennox-Gastaut syndrome, epileptic encephalopathy with continuous spike waves during sleep (CSWS), Landau-Kleffner syndrome. There is growing evidence that appropriate treatment may improve brain function, even when epilepsy is symptomatic  of brain damage. Epileptic encephalopathies do not exist in adults and require specific trials in children.
Performing randomized clinical trials (RCTs) in children may raise specific technical (biological sampling, assessment of drug effect), logistic (recruitment) and financial (cost considered to be high for a small market) as well as legal (informed consent) difficulties. Some specific controlled trials are performed in school-age children with focal epilepsy, but the younger age group and epileptic encephalopathies are neglected.
The European Agency of Medicines (EMA) encourages RCT alternative and innovative methodological approaches facilitating the drug evaluation in the whole paediatric population with pharmacoresistant epilepsy.
Epilepsy clinical trials unit
Clinical trials are conducted at our Neurology Unit in an in-patient and out-patient setting. The unit provides an ideal environment for clinical trials of new AEDs. The team is also regularly consulted by pharmaceutical companies and regulatory authorities on the design, logistics and scientific aspects of the evaluations of newer AEDs in children.
Pharmacokinetic studies are conducted in collaboration with Therapeutic Drug Monitoring Laboratory with Mass Spectrometry equipment.
The unit is overseen by the Ethics Committee of the Hospital and approval of this committee is required before any clinical trial can begin.